More than one million people in the United States get cancer each year. Although the five year survival rate has risen dramatically nearly fifty percent as a result of progress in early diagnosis and therapy, cancer still remains second only to cardiac disease as a cause of death in the United States. Breast, lung and bronchus, and colorectal cancer are the 3 most common cancers diagnosed in women, and in men, prostate, lung and bronchus, and colorectal cancers are the most commonly diagnosed. Designing effective treatments for patients with cancer still represents a major challenge.
Prostate cancer is the most common cancer in men and one of the leading causes of cancer death. Historically treatment of high-grade, recurrent prostate cancer has been to dramatically reduce the supply of androgens to the cancer via castration. Since signaling through the androgen receptor drives prostate cancer progression, removing the receptor's ligand (androgens) inhibits prostate cancer tumor growth, at least initially. However, resistance to androgen deprivation therapy (ADT) occurs in almost all patients leading to development of castrate resistant prostate cancer (CRPC). Resistance to ADT, and, in particular, the newest androgen receptor (AR)-directed therapies such as enzalutamide and abiraterone, is associated with expression of splice variants of the AR (AR-Vs) that are constitutively active. Directly targeting the AR-Vs has been problematic due to the intrinsically disordered nature of the AR N-terminus.